1. Field of the Invention
The present invention relates to a novel monoclonal antibody that binds specifically to a transmembrane 4 L six family member 5 (TM4SF5) protein, and more particularly, to a monoclonal antibody that binds specifically to a human TM4SF5 protein, a polynucleotide encoding the monoclonal antibody, an expression vector containing the polynucleotide, a transformant having the expression vector introduced therein, a method for preparing the monoclonal antibody, a composition containing the monoclonal antibody, a method for treating cancer or liver fibrosis using the monoclonal antibody, a method for inhibiting metastasis of cancer using the monoclonal antibody, a method for diagnosing cancer or liver fibrosis using the monoclonal antibody, a cancer diagnostic kit including the monoclonal antibody, and a liver fibrosis diagnostic kit including the monoclonal antibody.
2. Description of the Related Art
Generally, transmembrane 4 superfamily (TM4SF) proteins are a group of hydrophobic proteins having a molecular weight of about 25-50 kDa including four transmembrane domains, two extracellular loops, and two short cytoplasmic tail regions, also called tetraspanin or tetraspan. The TM4SF proteins form a complex on the cell membrane along with cell adhesion molecule such as integrin, thereby establishing a gigantic tetraspanin-enriched microdomain (TERM) and contributing to various biological functions such as cell adhesion, proliferation, and migration.
TM4SF5 (transmembrane 4 L six family member 5 or four-transmembrane L6 superfamily member 5) is a member of tetraspanin, and has a structure including four domains of non-soluble proteins which penetrate through cell membranes, two loops present extracellularly, one loop and two tails present in the cytoplasm. TM4SF5 is a homologue of the tumor-associated antigen L6 (TM4SF1), and mRNA of TM4SF5 is known highly overexpressed in the cells of pancreatic cancer, stomach cancer, colorectal cancer, soft tissue sarcoma, etc. Additionally, it was disclosed that an artificial expression of the TM4SF5 protein in COS7 cells could cause actin reorganization and focal adhesion turnover thus suggesting its involvement in cell migration (Lee S A et al., J Clin Invest 2008, 118(4):1354-66). Additionally, the TM4SF5 protein has a high amino acid sequence homology with L6, a cancer-related gene, and thus allegedly suspected as a cancer-associated gene, and also has been reported to be closely associated with the development and progress of cancer. TM4SF5 is involved in cell proliferation by promoting the progress of G1/S cycle through the intracellular p27Kip1 expression and activity of RhoA GTPase (Kim H et al., Biochim Biophys Acta 2010 1803(8):975-82), and the cross-talk in the signaling pathway between transforming growth factor-β1 (TGF-β1) and epidermal growth factor receptor (EGFR), the major factors involved in epithelial-mesenchymal transition (EMT), is known to induce the expression of TM4SF5, thereby bringing about the EMT (Kang M et al., Biochem J 2012 443(3):691-700).
As described above, with the emergence of TM4SF5 as a specific protein and anticancer target for a new cancer diagnosis, studies have been focused on diagnosing cancer having the TM4SF as a target. Additionally, for cancer treatment with the TM4SF as a target, studies have been focused on the inhibition of the biological activities of TM4SF5 in various fields. In particular, there have been studies on the compounds which can inhibit the activities of TM4SF5. For example, among chalcone compounds, sulfonamide- or sulfonate-substituted chalcone derivatives have been reported to inhibit the biological activities of TM4SF5 (KR Patent No. 10-0934706). In addition to the compounds which inhibit the biological activities of TM4SF5, the importance of the studies on the monoclonal antibodies that specifically bind to TM4SF5 has been emphasized. In particular, for clinical studies, there has been raised a need for the development of monoclonal antibodies that can be used for the prevention and treatment of cancer by specifically binding to TM4SF5 and thereby inhibiting the biological activities of TM4SF5.
The present inventors, while endeavoring to find a monoclonal antibody which can specifically bind to human TM4SF5 protein and effectively inhibit biological activities of TM4SF5 proteins such as cancer metastasis, developed monoclonal antibodies that binds specifically to a human TM4SF5 and confirmed that the antibodies can effectively inhibit the biological activities of TM4SF5, thereby completing the present invention.